The mouse double minute-2 gene (Mdm2) was initially identified in a screen for genes amplified on double minute chromosomes found in spontaneously transformed BALB/c 3T3 cells (Cahilly-Snyder et al., Somat. Cell Mol. Genet. 13:235-244 (1987)). When overexpressed, the Mdm2 has been demonstrated to immortalize rodent primary fibroblasts, to increase the rate of cellular proliferation, and to induce cellular transformation (Finlay, Mol. Cell Biol. 13:301-306 (1993)).
The human homolog, Hdm2, is an oncogene that is amplified in approximately one-third of human sarcomas and is overexpressed in a wide variety of other human cancers, including osteosarcomas, malignant fibrous histiocytomas, rhabdomyosarcomas, liposarcomas, leiomyosarcomas, glioblastomas, astrocytomas, myeloid leukemias, B-cell lymphomas, and oral squamous cell carcinomas (Oliner et al., Nature 358:80-83 (1992), Reifenberger et al., Cancer Res. 53:2736-2739 (1993), Bueso-Ramos, Blood 82:2617-2623 (1993), and reviewed in Bartel, Cell 2:9-15 (2002)). Given that p53 is perhaps the most commonly mutated gene in human cancers, and the absence of p53 mutations in many sarcomas that display Hdm2 amplification (Oliner et al., supra), it is likely that Hdm2-mediated inhibition of p53 is an important mechanistic step in the generation of these tumors, and overexpression of Hdm2 serves to inactivate p53 function in these tumors. Tumors have been identified that have both Hdm2 amplification and p53 loss (Cordon-Cardo et al., Cancer Res. 54: 794-799 (1994)). These rare sarcomas are much more aggressive than those tumors with alterations in only one of Fdm2 or p53, suggesting a p53-independent role for Hdm2 in these tumors.
Previous reports of analysis of a variety of human tumors that overexpress Hdm2 describe multiple, alternatively spliced forms of the Hdm2 message (Bartel et al., Int. J. Cancer 95:168-175 (2001)). In some cases, the presence of these spliced Hdm2 forms has been correlated with a more aggressive disease state (Matsumoto et al., Cancer Res. 58:609-613 (1998); Bartel et al., Cancer Cell 2:9-15 (2002)). Some of these transcripts encode Hdm2 proteins that lack the p53-binding domain and are incapable of complexing with p53, yet can induce foci formation in 3T3 cells in culture, suggesting that these tumor-isolated Hdm2 isoforms may contribute to transformation in a p53-independent manner (Sigalas et al., Nat. Med. 2:912-917 (1996)). Several spliced isoforms of Mdm2 and Hdm2 transcripts isolated from mouse or human tumors have been characterized, and many of these isoforms appear to inhibit cell proliferation, though the precise mechanism of growth inhibition remains unclear (Dang et al., Cancer Res. 62:1222-1230 (2002); Evans et al., Oncogene 20:4041-4049 (2001)).